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      Paclitaxel, Imatinib and 5-Fluorouracil Increase the Unbound Fraction of Flucloxacillin In Vitro

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          Abstract

          Flucloxacillin (FLU), an isoxazolyl penicillin, is widely used for the treatment of different bacterial infections in intensive care units (ICU). Being highly bound to plasma proteins, FLU is prone to drug-drug interactions (DDI) when administered concurrently with other drugs. As FLU is binding to both Sudlow’s site I and site II of human serum albumin (HSA), competitive and allosteric interactions with other drugs, highly bound to the same sites, seem conceivable. Knowledge about interaction(s) of FLU with the widely used anticancer agents paclitaxel (PAC), imatinib (IMA), and 5-fluorouracil (5-FU is scarce. The effects of the selected anticancer agents on the unbound fraction of FLU were evaluated in pooled plasma as well as in HSA and α-1-acid glycoprotein (AGP) samples, the second major drug carrier in plasma. FLU levels in spiked samples were analyzed by LC-MS/MS after ultrafiltration. Significant increase in FLU unbound fraction was observed when in combination with PAC and IMA and to a lesser extent with 5-FU. Furthermore, significant binding of FLU to AGP was observed. Collectively, this is the first study showing the binding of FLU to AGP as well as demonstrating a significant DDI between PAC/IMA/5-FU and FLU.

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          Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles.

          Felix Kratz (2008)
          Albumin is playing an increasing role as a drug carrier in the clinical setting. Principally, three drug delivery technologies can be distinguished: coupling of low-molecular weight drugs to exogenous or endogenous albumin, conjugation with bioactive proteins and encapsulation of drugs into albumin nanoparticles. The accumulation of albumin in solid tumors forms the rationale for developing albumin-based drug delivery systems for tumor targeting. Clinically, a methotrexate-albumin conjugate, an albumin-binding prodrug of doxorubicin, i.e. the (6-maleimido)caproylhydrazone derivative of doxorubicin (DOXO-EMCH), and an albumin paclitaxel nanoparticle (Abraxane) have been evaluated clinically. Abraxane has been approved for treating metastatic breast cancer. An alternative strategy is to bind a therapeutic peptide or protein covalently or physically to albumin to enhance its stability and half-life. This approach has been applied to peptides with antinociceptive, antidiabetes, antitumor or antiviral activity: Levemir, a myristic acid derivative of insulin that binds to the fatty acid binding sites of circulating albumin, has been approved for the treatment of diabetes. Furthermore, Albuferon, a fusion protein of albumin and interferon, is currently being assessed in phase III clinical trials for the treatment of hepatitis C and could become an alternative to pegylated interferon. This review gives an account of the different drug delivery systems which make use of albumin as a drug carrier with a focus on those systems that have reached an advanced stage of preclinical evaluation or that have entered clinical trials.
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            Pharmacokinetic issues for antibiotics in the critically ill patient.

            Jeffrey Lipman, Jason A Roberts (2009)
            To discuss the altered pharmacokinetic properties of selected antibiotics in critically ill patients and to develop basic dose adjustment principles for this patient population. PubMed, EMBASE, and the Cochrane-Controlled Trial Register. Relevant papers that reported pharmacokinetics of selected antibiotic classes in critically ill patients and antibiotic pharmacodynamic properties were reviewed. Antibiotics and/or antibiotic classes reviewed included aminoglycosides, beta-lactams (including carbapenems), glycopeptides, fluoroquinolones, tigecycline, linezolid, lincosamides, and colistin. Antibiotics can be broadly categorized according to their solubility characteristics which can, in turn, help describe possible altered pharmacokinetics that can be caused by the pathophysiological changes common to critical illness. Hydrophilic antibiotics (e.g., aminoglycosides, beta-lactams, glycopeptides, and colistin) are mostly affected with the pathphysiological changes observed in critically ill patients with increased volumes of distribution and altered drug clearance (related to changes in creatinine clearance). Lipophilic antibiotics (e.g., fluoroquinolones, macrolides, tigecycline, and lincosamides) have lesser volume of distribution alterations, but may develop altered drug clearances. Using antibiotic pharmacodynamic bacterial kill characteristics, altered dosing regimens can be devised that also account for such pharmacokinetic changes. Knowledge of antibiotic pharmacodynamic properties and the potential altered antibiotic pharmacokinetics in critically ill patients can allow the intensivist to develop individualized dosing regimens. Specifically, for renally cleared drugs, measured creatinine clearance can be used to drive many dose adjustments. Maximizing clinical outcomes and minimizing antibiotic resistance using individualized doses may be best achieved with therapeutic drug monitoring.
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              Clinical pharmacology of 5-fluorouracil.

              R Diasio, Richard Harris (1989)
              5-Fluorouracil, first introduced as a rationally synthesized anticancer agent 30 years ago, continues to be widely used in the management of several common malignancies including cancer of the colon, breast and skin. This drug, an analogue of the naturally occurring pyrimidine uracil, is metabolised via the same metabolic pathways as uracil. Although several potential sites of antitumour activity have been identified, the precise mechanism of action and the extent to which each of these sites contributes to tumour or host cell toxicity remains unclear. Several assay methods are available to quantify 5-fluorouracil in serum, plasma and other biological fluids. Unfortunately, there is no evidence that plasma drug concentrations can predict antitumour effect or host cell toxicity. The recent development of clinically useful pharmacodynamic assays provides an attractive alternative to plasma drug concentrations, since these assays allow the detection of active metabolites of 5-fluorouracil in biopsied tumour or normal tissue. 5-Fluorouracil is poorly absorbed after oral administration, with erratic bioavailability. The parenteral preparation is the major dosage form, used intravenously (bolus or continuous infusion). Recently, studies have demonstrated the pharmacokinetic rationale and clinical feasibility of hepatic arterial infusion and intraperitoneal administration of 5-fluorouracil. In addition, 5-fluorouracil continues to be used in topical preparations for the treatment of malignant skin cancers. Following parenteral administration of 5-fluorouracil, there is rapid distribution of the drug and rapid elimination with an apparent terminal half-life of approximately 8 to 20 minutes. The rapid elimination is primarily due to swift catabolism of the liver. As with all drugs, caution should be used in administering 5-fluorouracil in various pathophysiological states. In general, however, there are no set recommendations for dose adjustment in the presence of renal or hepatic dysfunction. Drug interactions continue to be described with other antineoplastic drugs, as well as with other classes of agents.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Antibiotics (Basel)
                Journal ID (iso-abbrev): Antibiotics (Basel)
                Journal ID (publisher-id): antibiotics
                Title: Antibiotics
                Publisher: MDPI
                ISSN (Electronic): 2079-6382
                Publication date (Electronic): 08 June 2020
                Publication date Collection: June 2020
                Volume: 9
                Issue: 6
                Electronic Location Identifier: 309
                Affiliations
                [1 ]Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, 93053 Regensburg, Germany; maximilianstolte@ 123456gmx.de (M.S.); weaam.abdulrahman@ 123456azhar.edu.eg (W.A.); Andre.Gessner@ 123456klinik.uni-regensburg.de (A.G.)
                [2 ]Department of Chemistry, University of Eastern Finland, FI-80100 Joensuu, Finland; janne.janis@ 123456uef.fi
                Author notes
                [* ]Correspondence: nahed.el-najjar@ 123456klinik.uni-regensburg.de ; Tel.: +49-941-944-14634
                Author information
                https://orcid.org/0000-0002-8446-4704
                Article
                Publisher ID: antibiotics-09-00309
                DOI: 10.3390/antibiotics9060309
                PMC ID: 7345279
                PubMed ID: 32521723
                SO-VID: 2dfca885-2507-4947-9c62-c683cdc05137
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 08 May 2020
                Date accepted : 04 June 2020
                Categories
                Subject: Article

                Keywords: albumin,α-1-acid glycoprotein,drug-drug interactions,anti-infective agents,ultrafiltration,cancer
                Data availability:
                Keywords: albumin, α-1-acid glycoprotein, drug-drug interactions, anti-infective agents, ultrafiltration, cancer

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